This application is a competitive renewal for 4 years of funding which extends earlier work conducted during the previous grant period. In this application we will enhance our understanding of the neurobiology of white matter changes in schizophrenia by introducing novel tools and methods that are more specific with respect to underlying pathology. This work is highly relevant to the overall VA mission, as patients with schizophrenia utilize 40% of the VA healthcare resources. Historically, the role of white matter in schizophrenia has been largely overlooked, with the majority of biological hypotheses focused on abnormalities in gray matter. This is despite the fact that schizophrenia is now viewed as a dys-connection syndrome, and that it is white matter that provides long-range communication among neurons. Only recently, with the introduction of diffusion MRI (dMRI), has attention slowly shifted to investigating the roe of white matter in schizophrenia. Nonetheless, findings to date have not led to an understanding of the etiology or to new pharmacological treatment(s), primarily because dMRI measures are nonspecific to underlying microstructural pathology. New methods, however, are more specific with respect to pathology, and based on our preliminary data using free-water derived from dMRI, and magnetic resonance spectroscopy (MRS), we hypothesize that white matter in schizophrenia is compromised by at least two distinct pathological processes that occur at different stages of the disease, i.e., neuroinflammation and neurodegeneration. Here we will use novel tools and methods to identify the neurobiological nature, time course, and functional consequences of specific changes in white matter in schizophrenia. Specifically, we will use several recently developed MRI acquisition and analysis methods, and apply them to both early onset schizophrenia and chronic schizophrenia populations, as well as to matched healthy controls. In terms of biological hypotheses, we predict that: A) early onset schizophrenia is likel associated with pathology (neuroinflammation) affecting extracellular volume observed using dMRI and magnetic resonance spectroscopy indicators of neuroinflammation; B) chronic schizophrenia is likely associated with increasing cellular pathology (neurodegeneration), observed using dMRI and MRS measures; and, C) both neuroinflammation and neurodegeneration have an effect on axonal conduction transmission speed, evinced using an interhemispheric transfer task, and localization of these changes will predict clinical profile. Longitudinal changes will also be evaluated one year later in the early psychosis patients in order to determine progressive changes in white matter over this time period. The investigation of dMRI, MRS, and EEG methods in schizophrenia will lead to novel findings of white matter abnormalities in schizophrenia, including new information about the role of neuroinflammation and neurodegenerative processes that occur at different stages of the disorder, which, in turn, will provide a new perspective on possible treatment interventions that will likely involve anti-inflammatory agents early in the course of illness.